comprehensive presentation on Rabies Prevention Concepts on pathogenesis, Active and Passive Immunisation

1. Understanding Rabies Disease and
Prevention
Dr (Lt Col) Ashutosh Ojha
151 Army Base Hospital,India
ashutosh8116@gmail.com
1

2. Section 1
Rabies disease background

3. 3
Benenson 1995
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Case fatality rate
Rabies is virtually 100% fatal
Treatment
100
90
80
70
60
50
40
30
20
10
0

4. Rabies
Rabies is an
ancient disease
Painting of a rabid dog
biting a man
Arabic
A.D. 1224
Baghdad school, by
Abdallah ibn al-Fadl
4
Picture courtesy of
Smithonian Institution,
Washington D.C.

5. The rabies virus
Taxonomy:
Family: Rhabdoviridae
Genus: Lyssavirus
Species: Rabies virus
bullet-shaped,
~180 nm long and
~75 nm wide
single-strand,
negative sense
RNA
5
CDC 2007; Bleck 2005

6. Pathogenesis: Exposure
Bite transmission
Human infection by rabies virus usually occurs as a
result of a transdermal bite from an infected wild or
domestic animal
Non-bite transmission
Scratches from a rabid animal
Saliva from a rabid animal comes into contact with a
victim’s mucous membranes or fresh skin lesions
Rare cases have been reported via:
Inhalation of virus-containing aerosols
Human-to-human transmission through
transplantation
6
1. Bleck 2005; 2. WHO 2004

7. How does the Rabies virus travel from wound
to brain

8. Human rabies: Clinical stages
Exposure
First
clinical
signs
First
neurologic
signs
Onset of
coma
Death
Incubation
period
Prodrome
phase
Acute
neurologic
phase
Coma
Usual
duration 20-90 days
2-10 days
2-7 days
0-14 days
Clinical
stage
Onset of rabies symptoms may start
rather late, ie, onset of symptoms
documented months, even years, after
exposure
Death usually occurs within a few days after the
appearance of clinical symptoms
8
1. Jackson 2007; 2. Hemachudha 2002

9. Clinical rabies in humans
Two forms of rabies are distinguished:
Furious (75-80%) (encephalitic; three-forth of all cases):
– Rabies transmitted from dogs is usually furious
Paralytic (20-25%) (dumb; one-fourth of all cases)
Clinical Presentation:
First clinical symptoms: non-specific, i.e., malaise, fever, and headache
Paresthesia: pain and abnormal feelings at the wound site are common
Acute neurologic phase: including throat spasms with an inability to swallow,
and anxiety, confusion, and hallucinations:
– Hydrophobia (only documented in humans),
respiratory spasms with aerophobia,
hyperactivity only exhibited with furious rabies
– Ascending paralysis or a symmetric quadriparesis only exhibited with
paralytic rabies
Coma and death
9
Jackson 2002

10. Rabies in children
Due to their short stature, children are susceptible
to bites on face, scalp, and upper part of the body
Children are more susceptible to animal bites
by playing in open grounds or in streets
Children cannot ward off animals easily
Children are more likely to provoke animals
Children might not report a bite or scratch
40-60% of all animal bite cases are reported to
occur in children <15 years of age
10
WHO 2008

11. Section 2
Epidemiology of rabies

12. Worldwide risk of rabies (2008)
No risk
12
WHO 2009
Low risk
Medium risk
High risk

13. India carries highest Rabies disease
burden
Estimated 20,000 human
rabies deaths per year
Principal reservoir of the
disease is dogs
No surveillance system of
rabies cases – lack of reliable
data
Estimated 27 million dogs –
although the number of stray
dogs is unknown
17.4 million dog bites annually
1. Cliquet 2007; 2. Sudarshan 2007
13

14. Rabies vaccines

15. Historical development of rabies vaccines
1885: Louis Pasteur developed the first rabies vaccine
Infected rabbit spinal cord partially inactivated by desiccation
1911: Semple vaccine; Sir David Semple improved Pasteur treatment
Inactivated virus using formalin and phenol
Infected adult rabbit, sheep, or goat brain tissue
Reactogenic, poorly immunogenic, up to 23 daily injections
1955: Fuenzalida vaccine; Drs Fuenzalida and Palacios
Suckling mouse brain (SMB) vaccine
Decreased reactogenicity with improved immunogenicity;
10-15 doses required
1956: Duck embryo vaccine; first effective cell-culture vaccine
Duck embryo vaccine (DEV)
Poorly immunogenic, high rate of allergic reactions. STOPPED 1980s
1970s: Modern cell-culture vaccines
Highly immunogenic with good safety profile
15
Plotkin 2008

16. Currently produced rabies vaccines I
Human diploid cell vaccines
(HDCV):
First-generation cell-culture
rabies vaccine
Virus grown on human
diploid cells, Pitman-Moore
strain
Good immunogenicity and
tolerability (hypersensitivity
reactions are however
reported with the unpurified
HDCV)2
Suitable for pre-exposure
vaccination and post-exposure
prophylaxis
†
Purified Vero cell rabies
vaccines (PVRV):
Second-generation cell-culture
rabies vaccine
Continuous cell line produced
on Vero cells (vervet monkey
origin), virus grown in microcarrier
system
Good immunogenicity and
tolerability
Clinical trials not permitted in the
US; no FDA approval due to risk
of residual DNA associated with
continuous cell line
Intradermal administration is currently licensed in India, the Philippines, Sri Lanka, Thailand, and Vietnam;
regulatory approval will continue to be adapted for other countries
16
1. Plotkin 2008; 2. CDC 1988

17. Currently produced rabies vaccines II
Purified chick embryo cell-culture vaccine (PCECV):
Second-generation cell-culture rabies vaccine
Prepared in primary chick embryo cells using Flury LEP
strain of fixed rabies virus
Good immunogenicity and tolerability
High purity and potency
Approved by the US FDA (intramuscular regimen only)
Recommended for each and every established WHO
vaccination schedule where intradermal administration
is licensed†
Intradermal administration is currently licensed in India, Myanmar
the Philippines, Sri Lanka, Thailand, and Vietnam;
regulatory approval will continue to be adapted for other countries
†
17
Plotkin 2008

18. WHO categories (I-III): Schedules for
post-exposure prophylaxis
Type of contact with a suspect or confirmed
rabid domestic or wilda animal, or animal
unavailable for testing
Type of
exposure
Recommended post-exposure prophylaxis
I
Touching or feeding animals, licks on
intact skin (ie, no exposure)
None
No prophylaxis is required
II
Nibbling of uncovered skin, minor
scratches or abrasions without bleeding
Minor
Administer vaccine immediately
III
Single or multiple transdermal bites or
scratches, licks on broken skin,
contamination of mucous membrane with
saliva from licks, exposures to bats
Severe
Administer rabies immunoglobulin and vaccine
immediately.
Category
18
1. WHO 2004; 2. CDC/ACIP 2008

19. Post-exposure prophylaxis
Wound treatment (all WHO categories)
Vaccine administration (WHO category II and III)
– Active immunization with highly immunogenic
rabies vaccine
RIG administration, if appropriate (WHO category III)
– Passive immunization followed by administration of
specific antibodies
19

20. Prevention of human rabies
The 5 Important Things
Magico-Religious Practices
(e.g. witchcraft, turmeric
powder etc.) DO NOT
HELP
Do not cover or Suture
the wound
Wash the wound
thoroughly with plenty of
water and soap
Apply an antiseptic
(povidone iodine) or even
alcohol
Vaccinate Immediately
e.g. Raibipur 1 mL IM

21. Rabies immunoglobulin (RIG)
RIG needs to be administered to all Category III wounds
along with complete course of ARV, 5 doses
(0,3,7,14,&,28 days) for 1st exposure
Subsequent exposure will require only 2 doses of ARV (0
& 3 days) and no RIG’s
RIG infiltrated in and around wounds
Two types of RIG
–
–
Human RIG,
dose 20 IU/kg of body weight
Equine RIG,
dose 40 IU/kg of body weight
RIG provides passive immunity
–
–
21
Immediate access to rabies virus-neutralizing
antibodies (RVNA)
Provides protection until active immunity begins
(7-10 days post-vaccination)
Courtesy Medi-Vision and
B. Quiambao, RITM, Manila

22. Prevention of human rabies
Vaccine administration
Post-exposure prophylaxis IM regimens:
– Essen regimen: 5 doses, 5 patient visits (DCGI
approved regimen)
– Zagreb regimen: 4 doses, 3 patient visits
Post-exposure prophylaxis ID regimens:
– Updated Thai Red Cross: 8 doses, 4 patient visits
(DCGI approved regimen)
– Thai Red Cross: 8 doses, 5 patient visits
– Oxford 8-site: 14 doses, 4 patient visits
22
1. WHO 2004; 2. WHO 2007
National Guidelines for Rabies Prophylaxis and Intra-dermal Administration of Cell Culture
Rabies Vaccines, 2007

23. Post-exposure prophylaxis IM administration:
Essen regimen
One IM dose of vaccine on Days 0, 3, 7, 14, and 28
1 mL (IM) into
deltoid (adults)
or into
anterolateral
area of thigh
(children)
5 doses – 5 visits
RIG is always recommended for transdermal wounds
23
1. WHO 2004; 2. WHO 2007

24. Post-exposure prophylaxis IM administration:
Updated Thai Red Cross (2-2-2-0-2)
Days 0, 3, 7, and 28 – two 0.1 mL doses
0.1 mL per site
Administered in right
and left deltoid
8 doses – 4 visits
RIG is always recommended for transdermal wounds
24
1. WHO 2004; 2. WHO 2007

25. DCGI recommended post-exposure
IM and ID regimens: Summary
Regimen
Day 0
Day 3
Day 7
Day 14
Day 21
Day 28
Day 90
Vials
Visits
Essen
1.0 mL
1.0 mL
1.0 mL
1.0 mL
–
1.0 mL
–
5
5
Day 0
Day 3
Day 7
Day 14
Day 21
Day 28
Day 90
mL
Visits
Thai Red
2x
2x
Cross
0.1 mL 0.1 mL
(updated)
2x
0.1 mL
–
–
2x
0.1 mL
–
<1
4
Regimen
National Guidelines for Rabies Prophylaxis and Intra-dermal Administration of Cell Culture Rabies Vaccines, 2007
25

26. Post-exposure prophylaxis in patients previously
vaccinated with a cell-culture rabies vaccine
Day
0
3
x1
x1
Two doses administered IM or ID Administered into (IM) or
above (ID) deltoid
No RIG is required
26
1. WHO 2004; 2. WHO 2007

27. National Guidelines for Rabies Prophylaxis and
Intra-dermal Administration of Cell Culture Rabies Vaccines
Intra-muscular (IM) Regimen
The currently available vaccines and regimen in India for post exposure
IM administration are described below.
Vaccines
1. Cell Culture Vaccines
 Human Diploid Cell Vaccine (HDCV)
 Purified Chick Embryo Cell Vaccine (PCEC)
 Purified Vero Cell Rabies Vaccine (PVRV)
2. Purified Duck Embryo Vaccine
Regimen
Essen Schedule: Five dose intramuscular regimen on days 0, 3, 7, 14
and 28.
National Guidelines for Rabies Prophylaxis and Intra-dermal Administration of Cell Culture Rabies Vaccines, 2007

28. National Guidelines for Rabies Prophylaxis and Intradermal Administration of Cell Culture Rabies Vaccines
Intra-dermal (ID) Regimens
General guidelines for use of IDRV
 Vaccines to be applied by intra-dermal route of administration should be approved by
DCGI.
 The vaccine package leaflet should include a statement indicating that the potency as well
as immunogenicity and safety allow safe use of vaccine by ID pre- and post-exposure.
 Post Marketing Surveillance (PMS) data should be maintained for minimum of two years by
vaccine manufacturers on a pre-designed and approved protocol.
 Intra-dermal injections must be administered by staff trained in this technique.
 Vaccine vials must be stored at 2º to 8ºC after reconstitution.
 The total content of reconstitute vial should be used as soon as possible, within 8 hours.
 Rabies vaccines formulated with an adjuvant should not be administered intra-dermally.
 Vaccine when given intra-dermally should raise a visible and palpable bleb in the skin.
 In the event that the dose is inadvertently given subcutaneously or intra-muscularly or in
the event of spillage, a new dose should be given intradermally in near by site.
 Animal bite victims on chloroquine therapy (anti-malarial therapy) should be given ARV by
intramuscular route.
National Guidelines for Rabies Prophylaxis and Intra-dermal Administration of Cell Culture Rabies Vaccines, 2007

29. National Guidelines for Rabies Prophylaxis and Intradermal Administration of Cell Culture Rabies Vaccines
DCGI approved ARV for use by intra-dermal route.
•
•
•
•
PVRV – Verorab, Aventis Pasteur (Sanofi Pasteur) India Pvt. Ltd.
PCECV – Rabipur, Chiron Behring Vaccines Pvt. Ltd.
PVRV – Pasteur Institute of India, Coonoor
PVRV – Abhayrab, Human Biologicals Institute.
Regimen
Updated Thai Red Cross Schedule (2-2-2-0-2).
This involves injection of 0.1ml of reconstituted vaccine per ID site and on two
such ID sites per visit (one on each deltoid area, an inch above the insertion
of deltoid muscle) on days 0, 3, 7 and 28
(Note: A DCGI order dated 9th August 2006, has revised the eligibility criteria for intradermal
administration of tissue culture rabies vaccines at anti- rabies clinics (ARC) in India from those
with a minimum attendance of 50 patients per day to those with a minimum of 10 patients per
day) National Guidelines for Rabies Prophylaxis and Intra-dermal Administration of Cell Culture Rabies Vaccines, 2007

30. Composition
Composition: one vial of powder and diluent for solution,
for one immunization dose (1 mL) contains:
Active ingredient:
– Rabies virus† (inactivated, Flury LEP strain ) potency ≥2.5 IU
Other ingredients‡
– Powder:
◦ TRIS-(hydroxymethyl)-aminomethane
◦ Sodium chloride
◦ Disodium edetate (Titriplex III)
◦ Potassium-L-glutamate
◦ Polygeline
†
◦ Sucrose
Produced on purified chick embryo cells;
‡May contain traces of neomycin,
– Diluent:
chlortetracycline, amphotericin B, and
chicken proteins
◦ Water for injection
30
Rabipur SmPC 2007
LEP: Low egg passage

31. Clinical database since 1981
More than 90 completed clinical trials
– More than 30 pre-exposure trials
– More than 50 post-exposure trials
– 7 booster trials
– 8 efficacy trials
Total: ~6000 subjects vaccinated
31
Rabipur Product Monograph 2008

32. PCECV Immunogenicity (Essen regimen)
100
GMC (IU/mL)
Adults administered IM
rabies vaccine on Days
0, 3, 7, 14, 30, and 90†
– Rabipur 1.0 mL
(n=15)
PCECV demonstrated
consistent and
high antibody
concentrations using
the standard WHO IM
regimen
Adverse reactions were
mainly mild (31.2%
systemic reactions,
56.5% local reactions)
10
1
‡
0.1
0
7
Scheiermann 1987
30
90
Time following immunization (days)
Current Essen regimen administration
is Days 0, 3, 7, 14, and 28
‡
0.5 IU/mL
†
33
14

33. Efficacy studies (IM)
No. of
Study subjects
(total)
No. of
subjects
bitten by
proven rabid
animals
Schedule/
vaccination
day
No. of
subjects
Follow-up
who received
period
RIG
(months)
Survival
rate after bite
by proven
rabid animal
(%)
1
45
45
IM (Essen)†
6 dose
45 (HRIG)
>12
100
2
28
28
IM (Essen)†
6 dose
28 (HRIG)
>6
100
3
21
21
IM (Essen)†
6 dose
4 (HRIG)
4
56
56
IM (Essen)†
6 dose
41 (ERIG)
19-34
100
5
1252
145
IM
2-6 dose
no RIG
>12
100
15
100
100% survival rate of subjects after exposure to
laboratory-confirmed rabid animals
Current Essen regimen administration
is Days 0, 3, 7, 14, and 28
†
34
References on note page

34. Immunogenicity following the Thai Red
Cross ID regimen
36
Briggs 2000
100
GMC (IU/mL)
Adults who had
received WHO
Category II and III
wounds administered
ID rabies vaccine on
Days 0, 3, and 7 (two
sites) and Days 30 and
90 (one site)
– PCECV 0.1 mL
– PVRV 0.1 mL
Rabipur is welltolerated and
immunogenic when
following the Thai Red
Cross ID regimen
PCECV
PVRV
10
1
†
0.1
0
7
14
30
90
Time following immunization (days)
†
0.5 IU/mL

35. Efficacy studies (ID)
No. of
subjects Category
No. of
Vaccination
No. of
Followexposed to
of
Study subjects
schedule subjects who up period
proven
contact
(total)
received RIG (months)
rabid
animals
Survival
rate (%)
1
148
148
I, II, or III
ID 2-site
(TRC)
<3% (ERIG)
≥12
100
2
113
113
III
ID 2-site
(TRC)
113
(HRIG/ERIG)
≥12
100
3
32
32
III
ID 8-site
12 (HRIG)
10 (ERIG)
36
100
100% survival rate of subjects after exposure to
laboratory-confirmed rabid animals
37
References on note page
†
All subjects received PCECV

36. Post-marketing Surveillance Study
38
Sehgal 1995
10
Subjects reporting adverse events (%)
In a post-marketing
surveillance study
(n=1252) with PCECV
– 4.0% reported
adverse events, all
were mild-tomoderate
Occurred mainly after
Dose 1 or 2 but
resolved spontaneously
within 48 hours
Mild fever was the most
common systemic
adverse event,
reported by 0.5% of
individuals
8
6
4
2.1%
1.1%
2
0
Injection-site pain
Injection-site
induration

37. Section 6
Summary

38. Summary - I
Rabies is a viral zoonosis that is transmitted from animals to
humans
– Human infection usually occurs as a result of a transdermal bite
or scratch from an infected animal
Dogs are the principal vector causing transmission of rabies to
humans in Africa, Asia, and parts of Latin America
There are no immediate clinical symptoms following exposure to
rabies virus
Rabies is almost invariably fatal following the onset of clinical
symptoms
Rabies is present throughout the world and >3 billion people are at
risk of infection in >100 countries
– The WHO estimates that the annual number of human rabies
deaths worldwide is ~55,000, and most occur in Asia and Africa
40

39. Summary - II
There are two active immunization strategies available to prevent
rabies in humans:
– Pre-exposure vaccination protects against potential exposure
to rabies particularly vulnerable children, individuals who live in
or travel to high-risk areas or work in high-risk occupations
– Post-exposure prophylaxis (PEP) is administered following
contact with a suspected or confirmed rabid animal. The WHO
and CDC provide guidelines for both strategies
PCECV is a purified chick embryo cell-culture rabies vaccine which
provides active immunization and protection
Approved by the US FDA (intramuscular regimen only)
Recommended for each and every established WHO vaccination
schedule where intradermal vaccination licensed†
Intradermal administration is currently licensed in India,
Myanmar, the Philippines, Sri Lanka, Thailand, and Vietnam;
regulatory approval will continue to be adapted for other countries
†
41

40. Summary - III
PCECV has been available for post-exposure and preexposure prophylaxis since 1984
The immunogenicity, efficacy, and safety profiles of
PCECV are well established and have been evaluated
in >90 clinical trials worldwide
42